Discovery of ONO-2920632 (VU6011887): A Highly Selective and CNS Penetrant TREK-2 (TWIK-Related K+ Channel 2) Preferring Activator Tool Compound.

Herein we describe our initial work on the KP family of potassium ion channels with the chemical optimization and characterization of a novel series of TWIK-Related K+ Channel (TREK)-1/2 dual activators and TREK-2 preferring activators derived from a high-throughput screening hit. The exercise provided TREK activators with good CNS penetration and others with low CNS exposure to enable exploration of both central and peripheral TREK activation. From this, ONO-2920632 (VU6011887 = ) emerged as a reasonably potent (human Tl; TREK-1 EC = 2.

K2.1 (TREK-1)-activator complexes reveal a cryptic selectivity filter binding site.

Polymodal thermo- and mechanosensitive two-pore domain potassium (K) channels of the TREK subfamily generate 'leak' currents that regulate neuronal excitability, respond to lipids, temperature and mechanical stretch, and influence pain, temperature perception and anaesthetic responses. These dimeric voltage-gated ion channel (VGIC) superfamily members have a unique topology comprising two pore-forming regions per subunit. In contrast to other potassium channels, K channels use a selectivity filter 'C-type' gate as the principal gating site.